Recent studies demonstrating clinical responses in autoimmune patients receiving therapies designed to target B-cells supports earlier preclinical data indicating a central role for B-cells in the pathology of autoimmunity. While existing strategies under development to target B-cells rely on global B-cell depletion, an ideal B-cell targeting therapeutic would specifically target activated B-cells while sparing resting B-cells from depletion. To address this clinical need we have applied a novel approach to suppress B-cell activation by leveraging an innovative therapeutic modality developed at MacroGenics termed Dual Affinity ReTargeting molecules (DARTs). Structurally, DARTs are bispecific diabodies stabilized with the incorporation of a disulphide bridge which can be expressed at high levels, are remarkably stable and do not suffer from the level of domain exchange and aggregation issues that have plagued other bispecific antibody based platforms. Furthermore they can be routinely purified, retain binding specificity and are potent in cell based assays. For the purpose of controlling autoimmunity, we have developed a DART drug candidate (CD32BxCD79B) comprised of dual specificity for B-cells by incorporating specificity for the B cell receptor (CD79B) and an inhibitory receptor (CD32B) to enable exploitation of physiologic negative signaling via activation-inhibition coupling for pharmacologic control of autoimmune disease. The mechanism of therapeutic intervention is therefore based on the forced coupling an inhibitory receptor with an activating receptor feasible through development of the DART platform. The CD32BxCD79B DART selectively binds B-cells with the designed specificity and is effective at inhibiting signaling through the B cell receptor resulting in blocking activated B-cell proliferation and immunoglobulin secretion. Using a surrogate CD32BxCD79B DART with mouse specificity we have shown efficacy in an animal model of autoimmunity. As the next step towards enabling commercialization of this product opportunity we are submitting this grant application to complete the necessary preclinical development and manufacturing processes required to file an investigational drug application. Upon completion of the work described in the grant application, MacroGenics will initiate clinical studies in systemic lupus erythematosus patients and assuming the phase I study safety endpoints are met, continue development of the CD32BxCD79B DART in lupus patients and other autoimmune indications. A development plan similar in scope to MacroGenics'lead clinical program (Teplizumab) presently in phase III clinical studies and partnered with Eli Lilly would then be implemented to complete the path towards commercialization. We believe that much in the way that TNF inhibitors revolutionized treatment of rheumatoid arthritis, B-cell inhibitors will form the next wave of biologic based autoimmune therapies with the product profile and mode of action of the CD32BxCD79B DART serving to at least augment if not supersede other B-cell inhibitory approaches. PUBLIC HEALTH RELEVANCE: Increasing evidence indicates a critical role for B lymphocytes in the pathology of autoimmune diseases including lupus, rheumatoid arthritis and multiple sclerosis. Through application of a novel therapeutic platform we have developed a novel strategy to leverage natural B lymphocyte processes to specifically inhibit over active B-cells and block autoimmunity. With appropriate funding we plan to complete studies necessary to enable clinical evaluation of this strategy in patients suffering from autoimmune disease.